Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
Department of Public Health Sciences, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
Nat Commun. 2020 May 15;11(1):2444. doi: 10.1038/s41467-020-16232-6.
The essential role of ORAI1 channels in receptor-evoked Ca signaling is well understood, yet little is known about the physiological activation of the ORAI channel trio natively expressed in all cells. The roles of ORAI2 and ORAI3 have remained obscure. We show that ORAI2 and ORAI3 channels play a critical role in mediating the regenerative Ca oscillations induced by physiological receptor activation, yet ORAI1 is dispensable in generation of oscillations. We reveal that ORAI2 and ORAI3 channels multimerize with ORAI1 to expand the range of sensitivity of receptor-activated Ca signals, reflecting their enhanced basal STIM1-binding and heightened Ca-dependent inactivation. This broadened bandwidth of Ca influx is translated by cells into differential activation of NFAT1 and NFAT4 isoforms. Our results uncover a long-sought role for ORAI2 and ORAI3, revealing an intricate control mechanism whereby heteromerization of ORAI channels mediates graded Ca signals that extend the agonist-sensitivity to fine-tune transcriptional control.
ORAI1 通道在受体引发的 Ca 信号中的基本作用已经得到很好的理解，但对于所有细胞中天然表达的 ORAI 通道三聚体的生理激活知之甚少。ORAI2 和 ORAI3 的作用仍然不清楚。我们表明，ORAI2 和 ORAI3 通道在介导生理受体激活诱导的再生 Ca 振荡中起着关键作用，而 ORAI1 在产生振荡中是可有可无的。我们揭示 ORAI2 和 ORAI3 通道与 ORAI1 形成多聚体，以扩大受体激活的 Ca 信号的敏感性范围，反映出它们增强的基础 STIM1 结合和升高的 Ca 依赖性失活。细胞将这种 Ca 流入的宽频带转化为 NFAT1 和 NFAT4 同工型的差异激活。我们的结果揭示了 ORAI2 和 ORAI3 的长期寻求作用，揭示了一种复杂的控制机制，其中 ORAI 通道的异源二聚化介导了渐变的 Ca 信号，从而扩展激动剂敏感性以微调转录控制。
